Water Molecules Increases Binding Affinity of Natural PI3Kγ Inhibitors Against Cancer

Area of Science:

• Biochemistry and Molecular Biology
• Pharmacology and Drug Discovery
• Computational Chemistry

Background:

• The Phosphoinositide 3-kinase (PI3K) pathway is crucial for cellular functions, including survival, protein synthesis, and metabolism.
• Dysregulation of the PI3K pathway is implicated in various cancers, making it a significant target for therapeutic intervention.
• Understanding inhibitor binding to PI3K targets is essential for developing effective anticancer drugs.

Purpose of the Study:

• To investigate the influence of water molecules on the binding orientation of PI3K inhibitors.
• To compare molecular docking results with crystallographic data, considering the presence and absence of water molecules.
• To evaluate the potential anticancer activity of serpentine as a PI3K inhibitor.

Main Methods:

• Employed molecular docking using AutoDock v4.2 to study PI3Kγ and its inhibitors (wortmannin, quercetin, myricetin, pyridyl-triazine, and serpentine).
• Performed docking simulations in both the presence and absence of water molecules within the binding pocket.
• Evaluated anticancer activity of serpentine through in vitro experiments.

Main Results:

• Docking studies revealed that the inclusion of water molecules in the binding pocket increases the binding affinity of PI3K inhibitors.
• Comparison of docking results with crystallographic data, considering binding energy, RMSD, and inhibition constant (Ki), supports the role of water molecules.
• Conserved and bridging water molecules play a significant role in enhancing inhibitor binding to PI3K targets.

Conclusions:

• Water molecules are critical for accurately modeling inhibitor binding to PI3K targets.
• Incorporating water molecules into docking protocols can improve the prediction of drug binding affinity and orientation.
• This finding has implications for the rational design of novel PI3K inhibitors with enhanced efficacy.